Arşiv Kaynak Tarama Dergisi
Archives Medical Review Journal
Larsen Syndrome
Larsen Sendromu
Ramachandran Sudarshan
1
Dept of Oral Medicine and Radiology, Sibar Institute of Dental Sciences, Guntur, India
ABSTRACT
Larsen syndrome is an inherited condition characterized by multiple joint dislocations and typical facial
features including depressed nasal bridge with hypertelorism and a prominent forehead. There are
only several cases reported since its first report by Larsen in 1950s. The aim of this review is to illustrate
the pathogenesis, clinical features, diagnosis, and differential diagnosis of this condition.
Key words: Larsen syndrome, joint dislocation, ultrasonography
ÖZET
Larsen sendromu çoğul eklem dislokasyonları, deprese burun köprüsü, hipertelorizm ve belirgin bir
alın ile karakterize tipik yüz özellikleri olan bir kalıtsal durumdur. İlk olarak 1950’li yıllarda bildirilmiş
olmasına karşın bildirilmiş olgu sayısı oldukça azdır. Bu yazının amacı, Larsen sendromunun
patogenezi, klinik özellikleri, tanı ve ayırıcı tanısı hakkında bilgi vermektir.
Anahtar kelimeler: Larsen sendromu, eklem dislokasyonu, ultrasonografi
Introduction
Larsen syndrome is a rare syndrome with genetic heterogeneity. It has both autosomal
dominant and autosomal recessive patterns of inheritance1. The filamins which is involved in
Larsen syndrome are cytoplasmic proteins that regulate the structure and activity of the
cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell
membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and
protein trafficking pathways are organized. Several mutations have been identified in the
gene encoding filamin B (FLNB gene) in individuals with autosomal dominant Larsen
Arşiv Kaynak Tarama Dergisi . Archives Medical Review Journal
2013; 22(1): 80-85
Sudarshan
81
syndrome2. Al-Kaissi et al. noted the presence of the syndrome in three generations of the
same family, which is suggestive of inheritance consistent with single-gene autosomal
dominance. They also reported that the multiple neonatal deaths in the family might
represent the higher expression of the syndrome2. This review briefly illustartes the features
and diagnosis of Larsen syndrome.
Mode of Inheritance
Latta suggested the following three possibilities to explain the mode of inheritance of the
syndrome3. These are;
1. The mother's anomaly may have been acquired and unrelated to the syndrome.
2. Larsen's syndrome might be inherited as an autosomal recessive trait, the mother being
heterozygous and displaying only minor manifestations.
3. Larsen's syndrome could be a single-gene, dominantly inherited disorder with wide
variability in severity. If the disease is inherited as a single-gene, autosomal dominant trait,
several other corollaries would follow. In one of these corollaries, the fully expressed gene
might result in higher rates of death in utero and during the neonatal period (this could
account for the apparent rarity of this syndrome). In the other one, the cases reported in the
literature in which neither parent nor siblings were involved might represent new mutations
which would then be passed on as a dominant gene.
Clinical Features
Larsen syndrome is characterized by multiple joint dislocations and unusual facies. The most
significant facial features are depressed nasal bridge with widely spaced eyes and a prominent
forehead. Cleft palate, hydrocephalus, cardiac malformations and abnormalities of spinal
segmentation are also described4. Further several other features have also been reported.
Spinal Anomalies
There are reports of cervical vertebrae hypoplasia, scoliosis, Khyphosis, wedge vertebrae,
spondylolysis, spina bifida oculta in Larsen syndrome 5.
Hands and Feet
Arşiv Kaynak Tarama Dergisi . Archives Medical Review Journal
82
Larsen Syndrome
Cylindrical fingers, spatulate thumbs, and short metacarpals could be observed in these cases.
Feet may have talipes equinovalgus or equinovarus deformity along with short metatarsals5.
Cardiovascular Anomalies
Thre are reports of aortic dialatation, atrial septal defect, ventricular septal defect, patent
ductus arteriosus, mitral valve prolapse and aneurysms of ductus arteriosus in Larsen
syndrome5.
Cartilages
Maldeveloped cartilage of the larynx and the tracheal rings (‘flabby cartilage’) may cause
respiratory difficulty6.
Craniofacial Anomalies
Marked frontal bossing typically flattened face, depressed nasal bridge; eyes widely set, small
mouth, and micrognathia7.
Oral
Oral features of Larsen syndrome are maxillary prognathism, malocclusion, supernumerary
teeth, macroglossia, microdontia, delayed dental development, hypodontia affecting all the
permanent canines, second and third molars, maxillary lateral incisors and second premolars;
morphological anomalies of the maxillary first premolars and molars; a class 3 skeletal pattern
and reduced upper facial height. Cephalometric radiographs showed the skull bones to have
an appearance similar to that of osteopetrosis8,9. Bilateral cleft lip and palate have also been
reported5.
Lethal Forms
A few lethal forms of Larsen syndrome inherited autosomal recessively have been described in
previous reports. One case with diaphragmatic hernia and a few cases with laryngomalacia
and apnea were described 5. At these cases, four different collagen fiber genes were analysed,
but no defected molecules could be detected despite the electrophoretic analysis with
fibroblast cultures. In two cases, multiple joint dislocations, tracheomalacia and lung
hypoplasia led to death by pulmonary failure in a short time have been reported. Abnormal
collagen bands were detected at these cases and described as collagen fiber dismaturity 5.
Arşiv Kaynak Tarama Dergisi . Archives Medical Review Journal
Sudarshan
83
Radiographic Findings
Radiographs reveal under-mineralisation and over-tubulation of the long bones, a bifid
calcaneus and advanced bone age in the carpal, or extra carpal bones7. Further radiographic
changes include dislocations, as previously noted. The distal phalanges are abbreviated. The
metacarpals and metatarsals are relatively shortened. Bone age is retarded. When the carpal
bones appear, they are irregular. There are from one to four supernumerary carpal bones in
75%. Abnormal segmentation and/or hypoplasia of cervical and thoracic vertebrae are
common. This may be associated with marked cervical kyphosis. In some cases, cervical
vertebral instability has led to quadriplegia or death. The vertebral bodies may be flattened. A
juxtacalcaneal accessory bone is present within the first four years of life in approximately
40%. It coalesces with the calcaneus by 5–8 years of age forming a bifid calcaneus that is
evident in lateral view. Additional centers of ossification may be seen at the elbow. The
proximal tibial epiphysis is often cone-shaped during development10.
Diagnosis
For antenatal diagnosis, targeted ultrasound in a fetus at risk for Larsen syndrome should
include evaluation of face, which tends to be flat, depressed nasal bridge, cleft palate,
hypertelorism and prominent forehead. Joints should be examined for club feet, multiple joint
dislocations at elbow, hips, knee and abnormal joint positions. Spinal abnormalities include
kyphosis and scoliosis. Occasional findings include hydrocephalus, clinodactyly,
supernumerary carpal bones and digits. Ultrasonographic diagnosis of the condition before
the end of the second trimester affords the patient the ability to terminate the pregnancy if
she desires, and gives the physician the chance to reevaluate the patient and plan for
appropriate management11.
In case of a late diagnosis, a cesarean section may be required to avoid birth trauma,
especially from cervical instability. The infant would need multidisciplinary care in the
neonatal intensive care unit12.
Differential Diagnosis
Otopalatodigital syndrome is most often mistaken for Larsen syndrome. In contrast, these
patients exhibit a pugilistic facies, hearing loss, paddle-shaped metatarsal bones, no
Arşiv Kaynak Tarama Dergisi . Archives Medical Review Journal
84
Larsen Syndrome
juxtacalcaneal bone, and no supernumerary carpal bones. Differential diagnosis also includes
arthrogryposis, fetal akinesia sequence, monosomy 21, Ehlers-Danlos syndrome, types VII and
XI, COFS syndrome, cleft palate, short stature, depressed nasal bridge, and sensorineural
hearing loss, spondyloepimetaphyseal dysplasia, Desbuquois syndrome and lethal Larsen-like
syndrome10.
Conclusion
Larsen syndrome requires a multispecialty approach with surgical corrections. Patient
counseling is essential to have a psychological support. Sonographic evaluation could play an
essential role for the management of this condition.
References
1.
2.
Gupta N, Kabra M. Larsen syndrome. Indian Pediatrics. 2008; 45:783-4.
Centre for Arab Genomic Studies. Larsen Syndrome, Autosomal Dominant.
http://www.cags.org.ae/pdf/150250.pdf. (Accessed: Aug 2012)
3. Habermann ET, Sterling A, Dennis RI, Bronx. Larsen's syndrome: a heritable disorder. J Bone Joint
Surg.1976; 58:558-61.
4. Orhan D, Balcı S, Deren O, Ütine EG, Başaran A, Kale G. Prenatally diagnosed lethal type Larsenlike syndrome associated with bifid tongue. Turk J Pediatrics. 2008; 50:395-9.
5. Kulkarni ML, Mohammed Z, Kulkarni PM. Larsen Syndrome- Lethal variety. Indian J Pediatr. 2005;
72:1053-4.
6. Kaya RA, Turkmenoglu O, Cavufioglu H, Dilbaz S, Aydin Y. Cervical pedicle screw fixation in a
patient with larsen syndrome: a case report. Turkish Neurosurgery. 2006;16:48-52.
7. Al-Kaissi A, Ammar C, Ghachema MB, Hammoub A, Chehidab FB. Facial features and skeletal
abnormalities in Lars en syndrome: a study of three generations of a Tunisian family. Swiss Med
Wkly. 2003; 133:625-8.
8. Perçin EF, Gedik R, Develioğlu H, Kunt T. Larsen's syndrome with dental anomalies: report of a
case. ASDC J Dent Child. 2002; 69:172-4.
9. Tsang MC, Ling JY, King NM, Chow SK. Oral and craniofacial morphology of a patient with Larsen
syndrome. J Craniofac Genet Dev Biol. 1986; 6:357-62.
10. Gorlin RJ, Cohen MM, Hennekam A. Syndromes of Head and Neck,4th Ed. New York, Oxford
University Press, 2001.
11. Kulkarni ML, Basha MH, Hegade S, Kumarasamy TA, Kulkarni AM. Antenatal diagnosis of Larsen
Syndrome. Indian J Pediatr. 2010; 77:819-20.
Arşiv Kaynak Tarama Dergisi . Archives Medical Review Journal
Sudarshan
85
12. Tongsong T, Wanapirak C, Pongsatha S, Sudasana J. Prenatal sonographic diagnosis of Larsen
syndrome. J Ultrasound Med. 2000; 19:419-21.
Correspondence Address / Yazışma adresi:
Ramachandran Sudarshan
Department of Oral Medicine and Radiology
Sibar Institute of Dental Sciences,
Guntur, India
E-mail: [email protected]
Arşiv Kaynak Tarama Dergisi . Archives Medical Review Journal